This study is designed to determine whether low-dose aspirin (acetylsalicylic acid, ASA) and standard anti-inflammatory doses of nabumetone (Relafen) can normalize the colorectal mucosal hyperproliferation found in patients with adenomatous polyps and cancers thus potentially preventing colorectal cancers. ASA and nabumetone are non-steroidal antiinflammatory drugs (NSAIDs) which act via inhibition of prostaglandin (PG) synthesis. High concentrations of PGs have been found in human colon cancer tissues, and NSMDs have been shown to arrest both transformed cell growth and that of primary tumor explants, as well as inhibit colonic tumor growth in animal models. Recent epidemiologic data suggest that ASA use may be associated with a decrease in colorectal cancer risk or mortality, while several small clinical studies suggest that NSAIDs may reduce the number of colonic polyps in patients with familial polyposis coli. We thus seek to determine whether ASA and/or nabumetone may decrease colonic mucosal proliferation and whether there is any correlation with a decrease in PGs. ASA was chosen because of its low cost, relative safety, large clinical experience, and recent studies showing its efficacy in primary and secondary prevention of myocardial and cerebrovascular thrombotic events, while nabumetone was chosen because it is a selective cyclooxygenase (COX)-2 inhibitor that causes little gastrointestinal toxicity. The study will enter 160 patients who have undergone polypectomy for removal of adenomas (of whom 120 will complete the study) into a randomized, placebo-controlled, double-blind, cross-over trial of aspirin (30 mg and 81 mg) and nabumetone (500 mg and 1000 mg), with each treatment cycle lasting 3 months. At the beginning and end of each 3-month cycle, rectal mucosal biopsy (with either sigmoidoscopy or colonoscopy) will be done and rectal mucosa will be assayed for PG contents and synthesis, as well as 5 colonic crypt biomarkers. Patients will also be monitored for potential toxicity via questionnaire, blood chemistries and blood counts, fecal occult blood and upper endoscopy (if warranted). Adherence will be monitored, including the use of serum ASA and thromboxane B2 levels, and an adherence reinforcement program will be in place. The two novel aspects of our study are: a) studying low-dose aspirin and b) comparing low-dose aspirin (which inhibits both COX-1 and COX-2) to nabumetone, a selective COX-2 inhibitor. This study will allow us to determine whether ASA or nabumetone will suppress colonic mucosal proliferation and whether there is any correlation with a decrease in PGs. Our study will establish an effective, nontoxic dose of ASA or nabumetone for a future full-scale randomized clinical trial. Our results will also increase our understanding of the biology underlying the potential preventive effect of NSAIDs, and may thus enable us to make more rational decisions on dose and duration of chemoprevention, and an optimal patient selection.